The invention relates to novel heterocyclic retinoid compounds and methods of synthesis thereof. The invention also relates to methods of using these heterocyclic retinoid compounds and pharmaceutical compositions thereof.
The retinoids are structural analogues of vitamin A and include both natural and synthetic compounds. Retinoid compounds such as all trans retinoic acid (xe2x80x9cATRAxe2x80x9d), 9-cis-retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid, 13-cis-retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells.
For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of hormone nuclear receptors that belong to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into the retinoic acid receptors (RAR) and the retinoid X receptors (RXR) each of which consists of three distinct subtypes (xcex1, xcex2 and xcex3).
ATRA is the natural ligand for the retinoic acid receptors and binds with similar affinity to the xcex1, xcex2 and xcex3 subtypes. A quantitative structure-activity relationship has been established for a number of synthetic RAR xcex1, xcex2 and xcex3 retinoid agonists, which has elucidated the principal electronic and structural characteristics that provide selective affinity for each RAR subtype (Douget et al., Quant. Struct. Act. Relat., 18, 107, 1999).
ATRA does not bind to RXR, for which 9-cis-retinoic acid is the natural ligand. A number of synthetic RXR and RAR xcex1, xcex2 and xcex3 retinoid agonists have also been described in the art (See, e.g., Billoni et al., U.S. Pat. No. 5,962,508; Belloni et al., WO 01/30326, published May 3, 2001; Klaus et al., U.S. Pat. No. 5,986,131; and Bernardon et al., WO92/06948, published Apr. 30, 1992). Other retinoid patents include Bernadon, U.S. Pat. Nos. 5,716,624 and 6,046,220.
In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne and hypertrophic cutaneous scars. Retinoids have also been used in the treatment of light and age damaged skin, the healing of wounds caused, for example, by surgery and burns (Mustoe et al., Science 237, 1333 1987; Sprugel et al., J. Pathol., 129, 601, 1987; Boyd, Am. J. Med., 86, 568, 1989) and as anti-inflammatory agents for treatment of arthritis. Other medicinal applications of retinoids include the control of acute promyelocytic leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. Retinoids have also been used extensively in treatment of premalignant epithelial lesions and malignant tumors (carcinomas) of epithelial origin (Bollag et al., U.S. Pat. No. 5,248,071; Spom et al., Fed. Proc. 1976, 1332; Hong et al., xe2x80x9cRetinoids and Human Cancerxe2x80x9d in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994, 597-630). However, many known retinoids lack selectivity and consequently exert harmful pleiotrophic effects that may cause patient death when used in therapeutically effective amounts. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, Chapters 63-64, 9th edition, 1996, McGraw-Hill.
Chronic Obstructive Pulmonary Disease (xe2x80x9cCOPDxe2x80x9d) refers to a large group of lung diseases which prevent normal respiration. Approximately 11% of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States.
COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema.
Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow.
Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmful agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (i.e., by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained. At least four different types of emphysema have been described according to their locations in the secondary lobule: panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema.
The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include, but are not limited to, chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema.
No effective methods for reversing the clinical indications of emphysema currently exist in the art. In some instances, medications such as bronchodilators, xcex2-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy.
Alveoli are formed during development by division of saccules that constitute the gas-exchange elements of the immature lung. The precise mechanisms governing formation of septa and their spacing remain currently unknown in primates. Retinoids such as ATRA, which is a multifunctional modulator of cellular behavior that may alter both extracellular matrix metabolism and normal epithelial differentiation, have a critical regulatory role in mammals such as the rat. For example, ATRA modulates critical aspects of lung differentiation through binding to specific retinoic acid receptors that are selectively temporally and spatially expressed. Coordinated activation of different retinoic acid receptors subtypes has been associated with lung branching, alveolization/septation and gene activation of tropoelastin in neonatal rats.
During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls (Liu et al., Am. J. Physiol. 1993, 265, L430; McGowan et al., Am. J. Physiol., 1995, 269, L463) and retinoic acid receptor expression in the lung peaks (Ong et al., Proc. Natl. Acad. of Sci., 1976, 73, 3976; Grummer et al., Pediatr. Pulm. 1994, 17, 234). The deposition of new elastin matrix and septation parallels depletion of these retinoic acid storage granules. Postnatal administration of retinoic acid has been shown to increase the number of alveoli in rats, which supports the concept that ATRA and other retinoids may induces alveoli formation (Massaro et al., Am. J. Physiol., 270, L305, 1996). Treatment of newborn rat pups with dexamethasone, a glucocorticosteroid, prevents septation and decreases expression of some sub-types of retinoic acid receptor. Supplemental amounts of ATRA have been shown to prevent dexamethasone inhibition of alveoli formation. Further, ATRA prevents dexamethasone from diminishing retinoic acid receptor expression and subsequent alveolar septation in developing rat lung.
ATRA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema (Massaro et al., Nature Med., 1997, 3, 675; xe2x80x9cStrategies to Augment Alveolization,xe2x80x9d National Heart, Lung, and Blood Institute, RFA: HL-98-011, 1998; Massaro et al., U.S. Pat. No. 5,998,486). However, the mechanism of action of ATRA in these studies remains undefined, although Massaro reports that ATRA generates new alveoli. More importantly, the use of ATRA presents several toxicity or adverse effects concerns.
Thus, novel retinoid agonists useful for treating dermatological disorders, disorders of the lung such as COPD, emphysema and cancer without the toxicity problems of ATRA or other retinoids are highly desirable.
The current invention provides novel heterocyclic retinoid compounds, methods of treating or preventing disorders of the lung such as chronic obstructive airway disorders, cancer and dermatological disorders, pharmaceutical compositions suitable for the treatment or prevention of such diseases or disorders and methods for delivering formulations of novel heterocyclic retinoid compounds into the lung of a mammal suffering from such diseases or disorders. In one embodiment, the present invention provides compounds according to structural formula (I): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
n is an integer from 0 to 2;
A is aryl or heteroaryl;
Bis O, S or NR6;
R6 is hydrogen or alkyl;
Y is xe2x80x94OR7, xe2x80x94SR7 or xe2x80x94NR8R9;
R7 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkyl-alkyl;
R8 and R9 are independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkyl-alkyl or together with the nitrogen atom to which they are attached form a heterocycloamino ring;
Z is xe2x80x94C(R101)2Oxe2x80x94, xe2x80x94R102Cxe2x95x90CR102xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(R103)2Sxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94C(O)NR10xe2x80x94;
each of R10, R101, R102 and R103 is independently hydrogen or alkyl;
R1 and R2 are independently hydrogen or alkyl;
R3 is hydrogen, alkyl; and
R4 and R5 are independently hydrogen, (C1-C8) alkyl or arylalkyl.
The present invention encompasses the use of the compounds of the invention to treat or prevent certain chronic obstructive airway disorders, particularly chronic obstructive pulmonary disease including chronic bronchitis, emphysema and asthma in mammals, especially humans that smoke or smoked cigarettes. In a preferred embodiment, the invention encompasses the treatment or prevention of panlobar emphysema, centrilobular emphysema or distal lobular emphysema in mammals using non-toxic and therapeutically effective doses of the compounds of the invention.
The present invention also encompasses the use of the compounds of the invention for treating or preventing cancer or dermatological disorders. Further, the instant invention encompasses the use of pharmaceutical compositions of the compounds of the invention to treat or prevent chronic obstructive airway disorders, cancer or dermatological disorders. Moreover, the invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of compounds of the invention into the lung of a mammal suffering from or at risk of chronic obstructive airway disorders or cancer.
The invention also encompasses the systemic use as well as the local use of the compounds of the invention or both in combination. Either or both can be achieved by the oral, mucosal or parenteral modes of administration. As mentioned above, means of delivering compounds of the invention directly into the lung by nebulizer, inhaler or other known delivery devices are encompassed by the invention. A method for treatingchronic obstructive airway disorders, cancer or dermatological disorders by combining compounds of the invention with one or more additional therapies is also encompassed by the invention.